Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
  • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
  • C07D217/18—Aralkyl radicals
  • C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine

Definitions

• ABSTRACT A tetrahydroisoquinoline compound of the formula:
• YE-R (I) wherein R is a trimethoxyphenyl, dimethoxyphenyl or methylene-dioxyphenyl radical, and pharmaceutically acceptable acid addition salts thereof.
• R is a trimethoxyphenyl, dimethoxyphenyl or methylene-dioxyphenyl radical, and pharmaceutically acceptable acid addition salts thereof.
• the compound (I) is prepared by condensing three-hydroxyphenethylamine with a phenylglycidic acid compound of the formula;
• the compound (I) may be prepared by dehydrating the compound of the formula;
• R has the same meaning as defined above, followed by hydrogenation of the resultant dihydroisoquinoline compound.
• the tetrahydroisoquinoline compounds (I) can be readily absorbed from digestive tracts and at the same time maintain their vasodilating activity for a long period of time.
• l-(3,4,5-trimethoxybenzyl)-6- hydroxy- 1 ,2,3,4-tetrahydroisoquinoline (hydrochloride) is administered duodenally to dogs at a dose of 300 rLg/kg, the increasing effect of the compound in the blood flow in the vertebral artery reaches to about 120 percent after 10 minutes of the administration, and said activity maintains for more than 1 hour.
• the tetrahydroisoquinoline compounds (I) also show a potent vasodilating activity on the common carotid artery.
• l-(3,4,5-trimethoxybenzyl)-6- hydroxy-1,2 ,3,4-tetrahydroisoquinoline (hydrochloride) enables to increase the blood flow in the common carotid artery of dog about 40percent when the compound is administered intravenously at a dose of 30 #g/kg.
• the toxicity of the tetrahydroisoquinoline compounds (I) is relatively low.
• the acute toxicity (LD of 1-(3,4,5-trimethoxybenzyl)-6-hydroxy- 1,2,3,4-tetrahydroisoquinoline hydrochloride, 'when administered to mice intravenously, is about 105 mg/kg.
• a tetrahydroisoquinoline compound of the formula (I) can be prepared by condensing 3-hydroxyphenethylamine with a phenylglycidic acid compound of the formula;
• Z is an alkyl radical or an alkali metal, and R has the same meaning as defined above.
• the condensation reaction may be accomplished by admixing 3-hydroxy-phenethylamine or its acid addition salt with the phenylglycidic acid compound (11) under an acidic condition.
• the reaction pH may be adjusted with a conventional acid such as hydrochloric acid, acetic acid, etc.
• Water, a water miscible organic solvent such as methanol, ethanol, propanol or a mixture thereof are suitable as the reaction solvent. It is preferred to carry out the reaction at 15 to C, especially at 20 to 30C.
• the tetrahydroisoquinoline compound (I) can be prepared by condensing 3-hydroxy-phenethylamine with a phenylacetic acid compound of the formula;
• R CH COZ (111) wherein Z is a hydroxy or alkoxy radical or a halogen atom and R has the same meaning as defined above, subjecting the resultant N-(3-hydroxyphenethyl)-2- phenylacetamide compound (IV) to intramolecular cyclization, and hydrogenating the resultant dihydroisoquinoline compound V).
• the condensation reaction of the first step can be accomplished in conventional manner.
• the phenylacetic acid compound (111) when employed in the form of free acid or alkyl ester, said reaction may be carried out by heating the mixture of the starting compounds at to 200C, especially at to 180C.
• the phenylacetic acid compound (III) when employed in the form of acid halide (e.g., acid chloride, acid bromide), the condensation reaction of the starting compounds may be carried out in the presence of an alkali agent in an aqueous solvenL 1n the latter case, it is preferred to carry out the reaction at 5 to 10C.
• said alkali agent are sodium hydroxide, sodium carbonate, sodium bicarbonate, pyridine, triethylamine etc. Water, a mixture of water and benzene or chloroform are suitable as the aqueous solvent.
• the intramolecular cyclization of the acetamide compound (1V) may be carried out in the presence of a dehydrating agent in a suitable solvent.
• a dehydrating agent Phosphorous oxychloride, phosphorus pentachloride, polyphosphoric acid or polyphosphoric esters may be preferably employed as the dehydrating agent.
• Benzene and toluene are suitable as the reaction solvent. It is preferred to carry out the reaction under refluxing.
• the subsequent hydrogenation reaction of the dihydroisoquinoline compound (V) can be accomplished in an appropriate procedure.
• the tetrahydroisoquinoline compound (I) may be readily obtained by hydrogenating the compound (V) with sodium borohydride or in the presence of a catalyst such as platinum, palladium or palladium-carbon.
• the hydrogenation of the compound (V) with sodium borohydride may be carried out in a solvent such as methanol, ethanol, aqueous methanol or aqueous ethanol.
• the catalytic hydrogenation of the compound (V) may be carried out under one to three atmospheric pressure in a solvent (e.g., Methanol, ethanol, water and a mixture thereof.)
• the tetrahydroisoquinoline compounds (I) thus obtained can be employed for the pharmaceutical purpose in both forms of bases and of their salts, which are readily convertible from one to the other by a conventional manner.
• Preferred examples of the pharmaceutically acceptable acid addition salts of the compounds (I) include inorganic acid addition salts such as hydrochloride, hydrobromide, perchloride, nitrate, sulfate, phosphate, and organic acid addition salts such as formate, acetate, propionate, glycollate, lactate, pyruvate, oxalate, malonate, succinate, maleate, fumarate, malate, citrate, tartrate, ascorbate, hydroxymaleate, benzoate, phenylacetate, aminobenzoate, methanesulfonate, ethanesulfonate, benzene-sulfonate, p-toluenesulfonate, sulfanilate, aspartate and glutamate
• Suitable excipients are substances that do not react with said tetrahydroisoquinoline compounds (1). Among these are included gelatin, lactose, glucose, sodium chloride, starch, magnesium stearate, talcum, vegetable oil, benzyl alcohol, gums or other known medicinal excipients.
• the pharmaceutical preparations may be in solid form such as tablets, coated tablets, pills or cupsules; or in liquid form'such as solutions, suspensions or emulsions. They may be sterilized and/or may contain auxiliaries, such as preserving, stabilizing, wetting or emulsifying agents. They may further contain other therapeutically valuable substances.
• EXAMPLE 1 4 g of 3-hydroxy-phenethylamine hydrochloride are dissolved in 250 ml of water. A solution of 7 g of sodium 3-(3,4,S-trimethoxyphenyl)-glycidate in 50 ml of water is added to the solution. Then, 9.3 ml of 10 percent hydrochloric acid and 9.3 ml of acetic acid are added to the mixture. The mixture is stirred for 140 hours at room temperature. After the reaction is completed, insoluble materials are removed by filtration. The aqueous layer is concentrated to dryness. Acetone is added to the residue, and precipitated crystals are collected by filtration. The crystals are recrystallized from 1 percent hydrochloric acid. 2.54 g of l-(3,4,5- trimethoxybenzyl)-6-hydroxyl ,2,3 ,4-
• a solution of 15.7 g of sodium 3-(3,4-methylenedioxyphenyl)-glycidate in 420 ml of water is added to the solution. Then, 24 ml of 10 percent hydrochloric acid and 20 ml of acetic acid are added to the mixture. The mixture is stirred for M4 hours at room temperature. After the reaction is completed, the mixture is concentrated to dryness. Acetone is added to the residue, and precipitated crystals are collected by filtration. After dryness, the crystals are recrystallized from water and then from a mixture of methanol and ether.
• a mixture of g of N-(3hydroxy-phenethyl)-2- (3,4,5-trimethoxyphenyl)-acetamide and 50 ml of phosphorous oxychloride is refluxed for 6 hours.
• the reaction mixture is evaporated under reduced pressure to remove the excess amount of phosphorus oxychloride.
• the residue is poured into ice water, and the aqueous solution is concentrated under reduced pressure.
• the residue thus obtained is dissolved in chloroform. After drying, the chloroform solution is evaporated to remove chloroform.
• the residual oil thus obtained is dissolved in 100 ml of 10 percent sodium hydroxide. Then, the aqueous solution is refluxed for an hour.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Other In-Based Heterocyclic Compounds (AREA)

Priority Applications (1)

Applications Claiming Priority (1)

Publications (1)

Family

ID=14610760

Family Applications (1)

Country Status (14)

Cited By (3)

Citations (5)

• 1971
  • 1971-12-07 ZA ZA718199A patent/ZA718199B/xx unknown
  • 1971-12-07 US US00205704A patent/US3818015A/en not_active Expired - Lifetime
  • 1971-12-10 GB GB5742771A patent/GB1327647A/en not_active Expired
  • 1971-12-14 CS CS7972*BA patent/CS163262B2/cs unknown
  • 1971-12-14 CS CS8678A patent/CS163261B2/cs unknown
  • 1971-12-16 DK DK617671AA patent/DK129237B/da unknown
  • 1971-12-16 ES ES398023A patent/ES398023A1/es not_active Expired
  • 1971-12-16 DE DE2162563A patent/DE2162563C3/de not_active Expired
  • 1971-12-16 CH CH1837471A patent/CH563982A5/xx not_active IP Right Cessation
  • 1971-12-16 NL NL7117290A patent/NL7117290A/xx not_active Application Discontinuation
  • 1971-12-16 FR FR7145329A patent/FR2118139B1/fr not_active Expired
  • 1971-12-16 HU HUTA1158A patent/HU162908B/hu unknown
  • 1971-12-17 SE SE00242/71*[A patent/SE367195B/xx unknown
  • 1971-12-17 CA CA130,365A patent/CA969962A/en not_active Expired
  • 1971-12-17 SE SE7401206A patent/SE387114B/xx unknown
  • 1971-12-17 AT AT1061672A patent/AT311973B/de active
  • 1971-12-17 AT AT1085971A patent/AT311972B/de not_active IP Right Cessation
• 1974
  • 1974-04-15 ES ES425325A patent/ES425325A1/es not_active Expired
• 1975
  • 1975-02-28 CH CH256675A patent/CH571498A5/xx not_active IP Right Cessation

Patent Citations (5)

Non-Patent Citations (2)

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